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Prof. drh. Hastari Wuryastuty, M.Sc., Ph.

D
Bag. I. Penyakit Dalam, FKH-UGM
Vitamin D
Fat soluble
Prohormone
Derived from cholesterol
Actually a group of analog steroid chemicals
Synthesis from sun exposure = Sunshine Vitamin
Insufficient sun exposure makes this a vitamin
Activated by enzymes in liver and kidneys
Responsible for proper utilization of Ca and P
Deficiency can cause diseases
Definitions
7-dehydrocholesterol: provitamin D
3
Previtamin D
3
: cholecalciferol
Vitamin D
3
: produced in the skin from irradiated
7-DHC, isomerized previtamin D
3
Vitamin D
2
: from plants, from irradiated
ergosterol


Vitamin D
Conditionally essential
Different chemicals,
produce same effect
Ergocalciferol (D2) Plant
sources & supplements
Cholecalciferol (D3)
Animal foods & made by
body
Sources of Vitamin D
RDA = 5 ug-15 ug
In foods:
Fortified milk, breads, cereals
Fish oils, salmon, sardines, herring, tuna
Livers, butter, egg (1 egg = 0.7 mcg),
margarine (1 tsp = 0.5 mcg)
Endogenous synthesis in the skin

Sources of Vitamin D
Body makes it own:
Dehydrocholesterol in the skin exposed to
sunlight
Energy transforms it into a pre-vitamin D
molecule
Body heat provides energy to change pre-
vitamin D into inactive Vitamin D

The Adequate Intake (AI) for
Vitamin D
5 ug/d (200 IU/day) for adults under age 51
10-15 ug/day (400 - 600 IU/day) for older
Americans
Light skinned individuals can produce
enough vitamin D to meet the AI from
casual sun exposure
Infant are born with enough vitamin D to
last ~9 months of age.
Vitamin D Synthesis
Vitamin D Synthesis
Absorption of Vitamin D
~80% of vitamin D consumed is absorbed
from micelles along with other fats
Absorbed in the distal small intestine and
transported via chylomicrons
Cholesterol from the skin is bound to DBP
and travels primarily to the liver through the
lymphatic system, but can be picked up by
other tissues (muscle and adipose)
Half-life in the blood 10-21 days.
Sources: sunlight
Main source of vitamin D is exposure to sunlight
whole body exposure 10-15 min midday sun in summer
(~1 MED) 15 000 IU (375 g) orally
exposure of hands, face and arms (~15% body surface) to
~1/3 MED should produce ~1000 IU
less vitamin D synthesised in winter, in those with dark
skin or older, and those who cover up for cultural reasons
or sun protection
amount of sun exposure to produce 1/3 MED varies with
latitude, season, time of day, skin type
short exposures to UV are more efficient: prolonged
exposure to high UV doses may degrade pre-vitamin D

Action spectra
UVB is the waveband required for vitamin
D synthesis
The action spectra for sunburn, cyclobutane
pyridine dimers all peak in the UVB range
With longer UVB exposure, vitamin D
synthesis does not continue, but DNA
damage does
SEASONAL CHANGES IN PTH AND CTx
- 1
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1
M o n t h
A
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u
d
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U V
2 5 O H D
P T H
C T x
J F M A M J J A S O N D
PHASE SHIFTS
1
0
- 1
M o n t h
A

m
p
l
i
t

u
d

e

U V
2 5 O H D
P T H
C T x
W r i s t f r a c t u r e s
H i p f r a c t u r e s
J F M A M J J A S O N D
UV exposure and skin damage
A balance is required between avoiding skin damage
(skin cancer & wrinkling) and maintaining adequate
vitamin D levels
Australia has highest reported rates of NMSC
Sun exposure causes ~99% NMSC and 95% melanoma
Sun protection required when UV index > 3
Deliberate sun exposure between 10am-2pm in summer
(11am 3pm Daylight saving time) is not advised
For regions south of 37
o
sun protection probably not
needed during June-July
Alternatives to UV exposure
Exposure of hands, face and arms to ~1/3 MED
of sunlight most days is considered adequate to
produce sufficient endogenous vitamin D
If adequate sunlight exposure is not possible, or
practical, then vitamin D supplementation is
recommended (at least 400 IU per day)
Because of high UV radiation, solaria are not
recommended for boosting vitamin D levels
(National Radiological Protection Board, 2002)

Metabolism and Storage of
Vitamin D
Activation by the liver and the kidneys (25-
OH D) and (1,25 OH2 D)
Stored in fat tissue
Activate vitamin D when calcium is
inadequate
Excretion of vitamin D mainly via bile
Functions of Vitamin D
Regulate blood calcium level
Vitamin D
Functions: Helps bone grow
Works in three ways:
1. Increases Calcium Absorption from the G.I.
tract.
2. Helps to withdraw calcium from bone.
3. Increases calcium retention in the kidney.
Vitamin D: Cell Differentiation
Vitamin D is able to influence
differentiation and function of the
some cells
Linked to reduction of breast, colon,
and prostate cancer development
Role in Bone Formation
Vitamin D creates a supersaturated Ca +
Phos solution
Causes Ca + Phos to deposit in the bones
Strengthen bones
Rickets is the result of low vitamin D
Osteomalacia (soft bone) is rickets in the
adult
Vitamin D as a Medicine
Type II (age-related) osteoporosis
Loss of bone mass
Limited ability to absorb vitamin D or produce it
10-20 ug vitamin D/ day plus calcium decrease
bone fracture
Risk for hypercalcemia
Psoriasis
Skin disorder
Topical treatment
Who is at risk for Deficiency ?
People at risk for vitamin D deficiency: those with
limited mobility
elderly (institutionalised or housebound)
disabled (motor or intellectual disability)
Dark skin (melanin)
Skin conditions, post-organ transplant where
sunlight avoidance is necessary
Fat Malabsorption



Who is at Risk for Deficiency?
Drug exposures that synthesis or
degradation 25OHD
Osteoporosis or minimal trauma fracture
Cultural or lifestyle choices
Vitamin D resistance
Resistance to the action of vitamin D
May be due to lack of calcitriol synthesis or
inability to bind to nuclear receptor
Requires large doses of calcitriol

Deficiency: rickets, osteomalacia
Interaction with other nutrients:
Calcium, phosphorus, vitamin K

Vitamin D Deficiencies
In children: Rickets
malformed bones, bow legs
In adults: osteomalacia most often occurs in
women with low Ca intake, repeated
pregnancies, low sun-exposure, and long
breastfeeding with infants
loss of Calcium from bone and change of shape
Causes of deficiency
Reduced intake or synthesis of cholecalciferol
sunlight: ageing, veiling, illness, immobility
synthesis for a given UV exposure: ageing, dark skin
as above combined with low dietary intake
Disorders associated with abnormal gut function and
malabsorption
small bowel disorders: coeliac disease, sprue, IBD, infiltrative
disorders, small bowel resection
pancreatic insufficiency: chronic pancreatitis, cystic fibrosis
biliary obstruction: 1 biliary cirrhosis, external biliary
drainage
Reduced synthesis or enhanced degradation of 25OHD
chronic hepatic disorders: hepatitis, cirrhosis
drugs: rifampicin, anticonvulsants
Vitamin D deficiency & bone
Mild
25OHD in range 25-50 nmol/L
increased PTH and high bone turnover
Moderate
25OHD in range 12.5-25 nmol/L
BMD, bone turnover, hip fracture risk
Severe
25OHD < 12.5 nmol/L
osteomalacia (rare in Australia)
bone and muscle pain, weakness and pseudofractures
thickened unmineralised seams
cortical thinning because 2 hyperparathyroidism

Vitamin D insufficiency
25-OH vitamin D level
Optimal concentration remains undecided
In a meta-analysis of fracture prevention in
the elderly, showed that fracture prevention
was greatest when 25-OH vitamin D levels
were ~100 nmol/L: these studies used oral
supplementation
This required vitamin D intakes of 700-800
IU/day, higher than currently recommended
doses
Vitamin D: Indications
Dietary supplement
Treatment of vitamin D deficiency
Treatment and correction of conditions
related to long-term deficiency: rickets,
tetany, osteomalacia
Prevention of osteoporosis
Forms of Vitamin D
calcifediol (Calderol)
calcitriol (Rocaltrol)
dihydrotachysterol (Hytakerol, DHT)
ergocalciferol (Calciferol)
Vitamin D supplementation
Some Ca and MV preparations contain
vitamin D (32-200 IU) too low
Halibut or cod liver oil capsules (400 IU
cholecalciferol) cheap but also contain
vitamin A (4000 IU)
Single pure vitamin D preparation in
Australia is Ostelin 1000 (1000 IU
ergocalciferol) @~24cents
Larger dose (50 000 IU) cholecalciferol
available in NZ

Supplementation and fractures
Greatest benefits: high-risk vitamin D-deficient
patients, with low BMD
Unlikely that supplementation effective in
vitamin D replete individuals but optimal
25OHD levels unknown: thresholds 50-110
nmol/L reported (Parfitt 1990, Mithal 2000)
Vitamin D examined in both 1
o
and 2
o
fracture
prevention trials but differences in baseline PTH
and 25OHD make comparisons difficult
Adequate calcium AND vitamin D likely to be
required to reduce fracture risk

Vitamin D supplementation
Prevention of fractures in the elderly
Prevention of falls in the elderly
Prevention of periodontal disease in the
elderly

Toxicity Warning
Vitamin D can be very toxic
Regular intake of 5-10x the AI can be toxic
Result from excess supplementation (not
from sun exposure or milk consumption)
Sign and symptoms: over absorption of
calcium (hypercalcemia), increase calcium
excretion
Calcium deposits in kidneys, heart, and
blood vessels
Mental retardation in infants
Vitamin D Toxicity:
Most potentially toxic of all vitamins!!!!
As little as 4 to 5 X RDA can be associated
with toxic symptoms
minor: diarrhea, headache, nausea
major: calcium deposits in soft tissues of heart,
kidney, arteries
Major concern: those who take Vitamin D
supplements
If some is good, more is NOT better!!!!!


Toxicity:
Not possible from excess
exposure to sunlight
Ultraviolet radiation is a carcinogen
Sun exposure is the major
environmental cause of skin cancer
BCC, SCC
Melanoma



Ambient UV, type and amount of
exposure and susceptibility
determine risk
Skin cancer risk is higher in susceptible populations living
closer to the equator
The higher the total lifetime amount of UV exposure, the
greater the risk of skin cancer
An intermittent pattern of intense exposure appears to
increase the risk of melanoma
People with sun-sensitive skin (i.e., burn easily, tan
poorly), blue eyes, many nevi are at greater risk of
developing skin cancer
UV: DNA damage
Cyclobutane pyrimidine dimers :
signature mutation
6-4 pyrimidine pyrimidone photoproducts
Single strand breaks
DNA protein crosslinks


UV: membrane damage
Lipid peroxidation
Activation of surface receptors with
induction of multiple signal transduction
pathways: alteration in activation of many
cellular proteins alteration in gene
expression and cellular function


UV induces an alteration in immune
surveillance
Decreased ability to eliminate cancerous
growths
Interference with development of contact
hypersensitivity




Public health message: sun
protection/skin cancer prevention
Shade
Clothing
Education
Public policy
Sunscreen use
Colorectal neoplasia
Epidemiologic data are generally consistent with
a protective effect of a higher 25(OH)D
concentration and higher vitamin D intake
The biologic basis for the sensitivity of
digestive malignancies to vitamin D status is
unclear
Randomized control studies are needed

Prostate and breast cancer
Studies have shown geographic gradients in
risk.
Case control studies and cohort studies have
shown a decreased risk of these diseases with
increased sunlight exposure
Hypothesis generating: Is it the vitamin D that
is protective?
The potential for cancer prevention by oral
intake of vitamin D must be tested in clinical
trials
Epidemiologic studies
Less evidence exists for a role for sunlight in:

Multiple sclerosis
Diabetes
Life is not so simple
Vitamin D is important for bone health
There is some data supporting vitamin D as
protective against certain diseases
Agreement on appropriate levels of 25-OH
vitamin D have not been established
Sunlight, a source of vitamin D, is a
carcinogen

Noncalcemic Functions of
1,25-dihydroxyvitamin D
Cytokines
Adaptive
Innate
Immune modulation
Immunomodulatory Effects of
1,25-dihydroxyvitamin D
What to do?
Some advocate for increased unprotected UV
exposure
This advice is complex: latitude, weather
dependent, time of day and season. It will not be
effective in higher latitudes during the winter
It is inefficient in the elderly, blacks
Many people (such as teenagers, many adults)
already are exposed to enough unprotected UV
exposure that more UV exposure will not be
helpful
What to do?
Many advocate for taking vitamin D
supplements
Advocate for increased fortification of
foods where it is not in place

What to do?

1. Many people do not avoid the sun, and
produce adequate vitamin D in the skin
depending on the time of year.
2. Incidental sun exposure throughout the
year likely produces adequate vitamin D
in the skin for many people
3. Vitamin D supplementation for those at
increased risk
What to do?
Further research on the role of sunlight and
vitamin D in cancer prevention
Randomized controlled trials of dietary
vitamin D as a cancer prevention agent

Sun protection messages
Remains important
Prevention of skin cancer and photoaging
Protection using hats, clothing, shade and
sunscreen during leisure time/occupational
exposure
Standard use of sunscreens has not caused
vitamin D deficiency

Benefits of Vitamin D
Skeletal-muscular
Strong muscles and bones
Infections
Prevent influenza, treat tuberculosis
Cancer
Prevent breast, colon, and prostate cancer
? Suppress metastasizes
Autoimmune Diseases
Prevent multiple sclerosis and type 1 diabetes
Cardiovascular Disease
Slow progression of atherosclerosis
Treat hypertension and congestive heart failure
Neuropsychiatric Disorders
Prevent schizophrenia and relieve depression